Amyloidosis: Symptoms, Types, Causes and Treatment

Amyloidosis is a rare but serious group of diseases caused by the abnormal accumulation of misfolded proteins—called amyloid—in tissues and organs. This build-up can disrupt normal organ function and lead to a wide range of symptoms, depending on which organs are affected. With advancing diagnostic tools and therapies, early recognition and tailored treatment are increasingly possible, but awareness and understanding remain crucial for improving outcomes.

Symptoms of Amyloidosis

Amyloidosis is notorious for its wide range of symptoms, which often mimic other, more common conditions. This makes early diagnosis challenging. Symptoms can vary not only by the type of amyloidosis but also by which organs are affected. However, a set of core symptoms and impacts are commonly reported, especially in systemic forms of the disease.

Symptom	Description	Common Organs Affected	Source(s)
Fatigue	Persistent tiredness, weakness	Systemic	2 5 7
Edema	Swelling, especially in legs/abdomen	Heart, kidneys	2 3 5 7
Neuropathy	Numbness, tingling, pain in extremities	Nerves	2 3 5 7
GI Symptoms	Diarrhea, constipation, weight loss	GI tract, liver	1 2 5 7
Dyspnea	Shortness of breath	Heart, lungs	2 3 5 7
Carpal Tunnel	Numbness, tingling in hands	Peripheral nerves	4 5 7
Proteinuria	Foamy urine, kidney damage	Kidneys	3 5 7
Macroglossia	Enlarged tongue	Oral cavity (AL type)	1 5
Purpura	Bruising, often around the eyes	Skin	5

Table 1: Key Symptoms of Amyloidosis

Overview of Symptom Presentation

Symptoms of amyloidosis are often subtle at first and can develop gradually. Fatigue and weakness are among the earliest and most universal complaints, frequently attributed to other conditions.

Organ-Specific Manifestations

• Heart (Cardiac Amyloidosis):
  • Leads to restrictive cardiomyopathy.
  • Presents with shortness of breath, swelling (edema), chest discomfort, and sometimes arrhythmias.
  • May also cause heart failure with preserved ejection fraction, which is a key diagnostic clue in adults 3 5 7 14.
• Kidneys:
  • Proteinuria (foamy urine) due to the leakage of proteins.
  • Swelling in legs and ankles.
  • May progress to nephrotic syndrome and kidney failure 3 5 14.
• Gastrointestinal Tract:
  • Diarrhea, constipation, weight loss, and sometimes bleeding.
  • Macroglossia (enlarged tongue) and GI pseudo-obstruction are classic but less common signs 1 2 5.
• Nervous System:
  • Peripheral neuropathy (numbness, tingling, pain in hands/feet).
  • Autonomic symptoms: dizziness, lightheadedness, erectile dysfunction, and gastrointestinal motility issues 2 3 5 7.
• Liver:
  • Hepatomegaly (enlarged liver), mild liver test abnormalities 1 14.
• Other:
  • Carpal tunnel syndrome is an early and common sign, especially in wild-type ATTR amyloidosis 4 5 7.
  • Easy bruising, particularly around the eyes (periorbital purpura) 5.

Psychological and Quality-of-Life Impacts

Patients often report significant emotional distress, including anxiety and depression, due to the chronic nature and unpredictability of the disease. The physical limitations imposed by organ dysfunction can also severely restrict daily activities and social participation 2.

Types of Amyloidosis

Amyloidosis is not a single disease but a spectrum of disorders, each defined by the specific protein that misfolds and forms amyloid deposits. Understanding the type is crucial, as treatment and prognosis vary significantly.

Type	Key Features	Typical Organs Affected	Source(s)
AL (Light Chain)	Most common; plasma cell disorder	Heart, kidneys, nerves, GI, liver	1 7 8 10
AA (Amyloid A)	Chronic inflammation-related	Kidneys, liver, spleen, GI	1 7 10 11
ATTRwt	Wild-type transthyretin; age-related	Heart, nerves, carpal tunnel	4 7 10
ATTRv	Hereditary transthyretin variant	Heart, nerves, GI, kidneys	7 10
Aβ2M	Dialysis-related	Joints, bones, tendons	10
Localized	Limited to a single organ	Skin, bladder, lungs, larynx	9 10

Table 2: Major Types of Amyloidosis

AL (Immunoglobulin Light Chain) Amyloidosis

• Cause: Produced by abnormal plasma cells that create misfolded light chains.
• Features: Most common systemic amyloidosis in developed countries.
• Organs Involved: Primarily heart and kidneys, but also nerves, liver, GI tract, and skin.
• Prognosis: Cardiac involvement is a major determinant of survival 1 7 8 13 15 16 17.

AA (Amyloid A) Amyloidosis

• Cause: Chronic inflammatory conditions lead to elevated serum amyloid A protein, which deposits as amyloid.
• Associated Diseases: Rheumatoid arthritis, chronic infections, autoinflammatory syndromes 1 10 11 12.
• Organs Involved: Mainly kidneys, but also liver, spleen, and GI tract.
• Trend: Becoming less common with better management of chronic inflammation 12.

ATTR Amyloidosis

• ATTRwt (Wild-type):
  • Cause: Age-related misfolding of normal transthyretin protein.
  • Features: Predominantly affects elderly men; underdiagnosed.
  • Symptoms: Heart failure, carpal tunnel syndrome 4 7 10.
• ATTRv (Variant/Hereditary):
  • Cause: Genetic mutations in transthyretin gene.
  • Features: Variable onset and organ involvement, often familial.
  • Symptoms: Neuropathy, cardiac involvement, sometimes GI symptoms 7 10.

Dialysis-Related (Aβ2M) Amyloidosis

• Cause: Accumulation of β2-microglobulin in patients on long-term dialysis.
• Features: Deposition mainly in bones, joints, and tendons 10.

Localized Amyloidosis

• Definition: Amyloid deposits are confined to a single tissue or organ.
• Common Sites: Skin, bladder, lungs, larynx; usually not life-threatening 9 10.

Causes of Amyloidosis

The root cause of amyloidosis is the misfolding of specific proteins that then aggregate and deposit as amyloid fibrils. However, the underlying triggers and risk factors differ according to type.

Type	Main Underlying Cause	Risk Factors/Associated Conditions	Source(s)
AL	Plasma cell dyscrasia	Multiple myeloma, MGUS	1 7 8 13
AA	Chronic inflammation	RA, IBD, chronic infections	1 7 10 11
ATTRwt	Age-related protein instability	Advanced age, male sex	4 7 10
ATTRv	Genetic mutations (TTR gene)	Family history	7 10
Aβ2M	Dialysis-related accumulation	Long-term hemodialysis	10
Localized	Local overproduction of protein	Variable; site-specific	9 10

Table 3: Causes and Risk Factors for Amyloidosis

Protein Misfolding: The Central Mechanism

At the heart of all types of amyloidosis is protein misfolding. Normally, proteins fold into precise shapes for proper function. In amyloidosis, certain proteins—because of genetic mutations, chronic inflammation, or aging—misfold and aggregate, forming insoluble amyloid fibrils that deposit in tissues 6 10.

AL (Light Chain) Amyloidosis

• Underlying Disease: Caused by a small clone of plasma cells producing abnormal immunoglobulin light chains that misfold.
• Risk Factors: Plasma cell disorders such as multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS) 1 7 8 13.
• Pathway: The overproduced light chains circulate in the blood, misfold, and deposit as amyloid.

AA (Amyloid A) Amyloidosis

• Underlying Disease: Prolonged elevation of serum amyloid A due to chronic inflammation.
• Strong Associations: Rheumatoid arthritis, inflammatory bowel disease, chronic infections (e.g., tuberculosis, osteomyelitis), and certain cancers 1 11 12.
• Mechanism: Persistent inflammation stimulates the liver to produce high levels of serum amyloid A, which aggregates and deposits in tissues.

ATTR Amyloidosis

• Wild-type (ATTRwt): Occurs with age, most often in elderly men, due to the instability of the normal transthyretin (TTR) protein 4 7 10.
• Hereditary (ATTRv): Inherited mutations in the TTR gene lead to amyloidogenic variants 7 10.

Dialysis-Related (Aβ2M) Amyloidosis

• Mechanism: Inadequate removal of β2-microglobulin in patients on long-term dialysis causes its accumulation and deposition 10.

Localized Amyloidosis

• Mechanism: Local overproduction of an amyloidogenic protein at a specific site, such as the larynx or urinary tract, often with no systemic involvement 9 10.

Treatment of Amyloidosis

Treatment strategies for amyloidosis focus on halting the production of the amyloid-forming protein, managing symptoms, and—where possible—removing existing amyloid deposits. The specific approach depends critically on the amyloidosis type and the extent of organ involvement.

Amyloidosis Type	Main Treatment Approach	Example Therapies	Source(s)
AL	Suppress abnormal plasma cells	Chemotherapy, stem cell transplant, proteasome inhibitors, immunotherapies	1 7 8 13 15 16 17
AA	Control underlying inflammation	Anti-inflammatory drugs, treat underlying disease	1 7 11 12
ATTRwt/ATTRv	Stabilize TTR, gene silencing	Tafamidis, patisiran, inotersen, liver transplant (for ATTRv)	7 14
Aβ2M	Improve dialysis modalities	High-flux dialysis, kidney transplant	10
Localized	Site-specific interventions	Surgical removal, radiotherapy	9 10

Table 4: Treatment Strategies for Amyloidosis

AL (Light Chain) Amyloidosis

• Goal: Eliminate the source of amyloidogenic light chains.
• First-Line Treatments:
  • Chemotherapy targeting plasma cells (e.g., bortezomib, melphalan, cyclophosphamide).
  • Autologous stem cell transplantation for eligible patients 1 7 8 13 15 16 17.
• Novel Therapies:
  • Proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies (e.g., daratumumab).
  • Combination regimens based on cardiac and renal risk stratification.
• Supportive Care: Management of organ dysfunction (heart failure, kidney failure) is vital.

AA (Amyloid A) Amyloidosis

• Goal: Suppress chronic inflammation to reduce serum amyloid A production.
• Approach:
  • Aggressive treatment of underlying conditions (e.g., rheumatoid arthritis) with disease-modifying antirheumatic drugs or biologics.
  • Infection control if underlying cause is infectious 1 11 12.
• Outcome: Improved control of inflammation can halt or even reverse organ damage in some cases.

ATTR Amyloidosis

• Stabilizers: Tafamidis binds to TTR and prevents its misfolding, approved for both wild-type and hereditary ATTR 7 14.
• Gene Silencers: Patisiran and inotersen reduce TTR production in the liver (mainly for hereditary ATTRv) 7 14.
• Liver Transplant: Considered in select hereditary cases to replace the source of mutant TTR 7.
• Supportive Management: Cardiac and neurological symptom control is essential.

Dialysis-Related (Aβ2M) Amyloidosis

• Approach: Use of high-flux dialysis membranes and, where possible, kidney transplantation to remove β2-microglobulin 10.

Localized Amyloidosis

• Treatment: Usually surgical excision or site-specific interventions, as systemic therapy is rarely needed 9 10.

Emerging Therapies and Future Directions

• Immunotherapies: Drugs that target and promote clearance of amyloid deposits are under investigation, especially for AL and ATTR amyloidosis 7 8 13 15.
• RNA Inhibitors and Stabilizers: Expanding the therapeutic landscape, offering hope for more types and stages of disease 7.
• Early Diagnosis and Personalized Medicine: Advances in imaging, biomarkers, and risk-adapted treatment are improving outcomes, but early detection remains a challenge 7 15 16 17.

Conclusion

Amyloidosis is a rare but complex disease, marked by the abnormal build-up of misfolded proteins that can damage nearly any organ system. Timely recognition and precise classification are crucial, as treatment and prognosis depend heavily on the amyloidosis type and organ involvement.

Key Points:

• Amyloidosis presents with a broad range of symptoms, often mimicking other diseases and leading to delayed diagnosis.
• The main types include AL (light chain), AA (inflammatory), ATTR (wild-type and hereditary), dialysis-related, and localized amyloidoses.
• Causes vary: from plasma cell disorders and chronic inflammation to genetic mutations and long-term dialysis.
• Treatment is tailored to the amyloid type:
  • AL: Chemotherapy, stem cell transplant, and novel immunotherapies.
  • AA: Control of the underlying inflammatory or infectious disease.
  • ATTR: Protein stabilizers, gene silencers, and sometimes liver transplant.
  • Dialysis-related and localized forms have unique management strategies.
• Early diagnosis and risk-adapted therapy are improving survival and quality of life, but awareness and multidisciplinary care remain essential.

Amyloidosis, once considered uniformly fatal, is now increasingly treatable with modern diagnostics and therapies—offering hope for those affected by this challenging set of diseases.